Rapid point-of-care detection of SARS-CoV-2 infection in exhaled breath using ion mobility spectrometry: a pilot study.

BACKGROUND: An effective testing strategy is essential for pandemic control of the novel Coronavirus disease 2019 (COVID-19) caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Breath gas analysis can expand the available toolbox for diagnostic tests by using a rapid, cost-beneficial, high-throughput point-of-care test. We conducted a bi-center clinical pilot study in Germany to evaluate breath gas analysis using multi-capillary column ion mobility spectrometry (MCC-IMS) to detect SARS-CoV-2 infection. METHODS: Between September 23, 2020, and June 11, 2021, breath gas measurements were performed on 380 patients (SARS-CoV-2 real-time polymerase chain reaction (PCR) positive: 186; PCR negative: 194) presenting to the emergency department (ED) with respiratory symptoms. RESULTS: Breath gas analysis using MCC-IMS identified 110 peaks; 54 showed statistically significant differences in peak intensity between the SARS-CoV-2 PCR-negative and PCR-positive groups. A decision tree analysis classification resulted in a sensitivity of 83% and specificity of 86%, but limited robustness to dataset changes. Modest values for the sensitivity (74%) and specificity (52%) were obtained using linear discriminant analysis. A systematic search for peaks led to a sensitivity of 77% and specificity of 67%; however, validation by transferability to other data is questionable. CONCLUSIONS: Despite identifying several peaks by MCC-IMS with significant differences in peak intensity between PCR-negative and PCR-positive samples, finding a classification system that allows reliable differentiation between the two groups proved to be difficult. However, with some modifications to the setup, breath gas analysis using MCC-IMS may be a useful diagnostic toolbox for SARS-CoV-2 infection. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov on September 21, 2020 (NCT04556318; Study-ID: HC-N-H-2004).

[Prospective monitoring of a university rheumatology outpatient clinic throughout the first wave of the COVID-19 pandemic : What lessons can be learned?] / Prospektive Verlaufsbeobachtung einer universitären Rheumaambulanzkohorte während der ersten Welle der COVID-19-Pandemie : Welche Lehren kann man ziehen?

BACKGROUND: In March 2020 the SARS-CoV­2 pandemic disseminated initially especially in Bavaria. At that time data on patients with rheumatic diseases and immunomodulatory treatment was lacking. OBJECTIVE: The aim was to analyze the influence of the SARS-CoV­2 pandemic on the clinical treatment strategy. MATERIAL AND METHODS: Between 16 March and 31 July 2020 all patients who consecutively presented at the rheumatology outpatient clinic of the Klinikum rechts der Isar of the Technical University of Munich were included in the study. Individual treatment adjustments were based on clinical judgment and the recommendations for action of the German Society for Rheumatology (DGRh). RESULTS: A total of 322 patients were included. The most frequent diagnosis was rheumatoid arthritis with 17%, ANCA-associated vasculitis (AAV) with 14% and SLE with 12%. Of the patients 262 were on DMARD treatment and 77 received oral glucocorticoids. There were 5 cases of suspected SARS-CoV­2 infection; however, no patient verifiably became ill due to COVID-19. In 40 patients, treatment adjustments were done due to the pandemic, whereby 3 patients developed a flare of the underlying disease. In retrospect, treatment de-escalation occurred most frequently in AAV, IgG4-related disease, immunosuppressive treatment with rituximab and the simultaneous presence of malignant diseases. CONCLUSION: The total lack of confirmed SARS-CoV­2 infections in an otherwise strongly affected region could indicate that the infection risk for SARS-CoV­2 is not substantially increased for patients with inflammatory rheumatic diseases. A continuation of most immunosuppressive medications therefore seems reasonable during the ongoing pandemic.

Dose profiles and x-ray energy optimization for microbeam radiation therapy by high-dose, high resolution dosimetry using Sm-doped fluoroaluminate glass plates and Monte Carlo transport simulation.

Microbeam radiation therapy (MRT) utilizes highly collimated synchrotron generated x-rays to create narrow planes of high dose radiation for the treatment of tumors. Individual microbeams have a typical width of 30-50 µm and are separated by a distance of 200-500 µm. The dose delivered at the center of the beam is lethal to cells in the microbeam path, on the order of hundreds of Grays (Gy). The tissue between each microbeam is spared and helps aid in the repair of adjacent damaged tissue. Radiation interactions within the peak of the microbeam, such as the photoelectric effect and incoherent (atomic Compton) scattering, cause some dose to be delivered to the valley areas adjacent to the microbeams. As the incident x-ray energy is modified, radiation interactions within a material change and affect the probability of interactions, as well as the directionality and energy of ionizing particles (electrons) that deposit energy in the valley regions surrounding the microbeam peaks. It is crucial that the valley dose between microbeams be minimal to maintain the effectiveness of MRT. Using a monochromatic x-ray source with x-ray energies ranging from 30 to 150 keV, a detailed investigation into the effect of incident x-ray energy on the dose profiles of microbeams was performed using samarium doped fluoroaluminate (FA) glass as the medium. All dosimetric measurements were carried out using a purpose-built fluorescence confocal microscope dosimetric technique that used Sm-doped FA glass plates as the irradiated medium. Dose profiles are measured over a very a wide range of x-ray energies at micrometer resolution and dose distribution in the microbeam are mapped. The measured microbeam profiles at different energies are compared with the MCNP6 radiation transport code, a general transport code which can calculate the energy deposition of electrons as they pass through a given material. The experimentally measured distributions can be used to validate the results for electron energy deposition in fluoroaluminate glass. Code validation is necessary for using transport codes in future treatment planning for MRT and other radiation therapies. It is shown that simulated and measured micro beam-profiles are in good agreement, and micrometer level changes can be observed using this high-resolution dosimetry technique. Full width at 10% of the maximum peak (FW@10%) was used to quantify the microbeam width. Experimental measurements on FA glasses and simulations on the dependence of the FW@10% at various energies are in good agreement. Simulations on energy deposited in water indicate that FW@10% reaches a local minimum around energies 140 keV. In addition, variable slit width experiments were carried out at an incident x-ray energy of 100 keV in order to determine the effect of the narrowing slit width on the delivered peak dose. The microbeam width affects the peak dose, which decreases with the width of the microbeam. Experiments suggest that a typical microbeam width for MRT is likely to be between 20-50 µm based on this work.

Acetogenin-Based Formulated Bioinsecticides on Anastrepha fraterculus: Toxicity and Potential Use in Insecticidal Toxic Baits.

The present study evaluated the lethal toxicity and oviposition deterrence of ethanolic extracts of Annona mucosa Jacq., Annona muricata L., and Annona sylvatica A. St.-Hil on Anastrepha fraterculus (Wiedemann) (Diptera: Tephritidae) compared with those of a limonoid-based bioinsecticide (Azamax™ 1.2 EC-azadiractin +3-tigloyl-azadiractol) and a synthetic spinosyn-based insecticide (Delegate™ 250 WG-spinetoram). In addition, the efficacy of the selected toxic bait formulations was evaluated by mixing them with food attractants (Anamed™, 3% Biofruit and 7% sugarcane molasses). In the topical application and ingestion bioassays (2000 mg L-1), the aqueous emulsion of the A. mucosa extract caused greater than 80% mortality of A. fraterculus adults in a similar manner to the spinosyn-based synthetic insecticide. Concentration-response curves were performed for the most promising treatments and showed an activity level dependent on the mode of contamination, exposure time, and applied concentration. In bioassays with and without choice, the A. mucosa (77%), A. muricata (51%), A. sylvatica (60%), Azamax™ (74%), and Delegate™ 250 WG (100%) significantly reduced the number of punctures and galleries in grape berries. In combination with the food attractants Anamed™, 3% Biofruit, and 7% sugarcane molasses, the emulsion of the A. mucosa extract had a residual effect similar to that of the spinetoram insecticide, with a mortality rate of over 80% of A. fraterculus adults up to 14 days after application (DAA) in the absence of rain. Thus, acetogenin-rich formulations, especially from A. mucosa seeds, are useful alternatives for the integrated management of A. fraterculus in agricultural orchards.

4G versus 3G-enabled telemedicine in prehospital acute stroke care.

BACKGROUND: Time to reperfusion treatment is closely related to outcome in ischemic stroke. Prehospital stroke work-up in CT-equipped mobile stroke units is effective in reducing time to thrombolytic treatment. Current evidence predominantly comes from mobile stroke units staffed with neurologists but telemedicine-guided management may be acceptable for providing neurological expertise in ambulances. With unsatisfactory experiences in third-generation (3G)-based approaches, fourth-generation (4G) networks may provide adequate audio-visual quality but systematic comparisons of technological parameters and decision-making are lacking. METHODS: Trained actors presented stroke symptoms and paramedics assisted the remotely guided extended National Institutes of Health Stroke Scale (eNIHSS) assessment on the mobile stroke unit in Berlin, Germany. We compared technical parameters of 4G and 3G connections, assessed audio-visual quality of examination, and analyzed reliability of neurological assessment and treatment decisions made by the remote neurologist versus the mobile stroke unit neurologist. RESULTS: 4G and 3G connections were evaluated in 40 scenarios each. Connectivity was not available in 17% of 4G- and 15% of 3G-attempts with 6% simultaneous unavailability of both networks. The remote examiners graded audio and video quality in 4G better than in 3G with slightly shorter assessment duration in 4G (mean: 9 (SD:5) vs. mean 11 (SD:3) min, p = 0.10). Reliability of the eNIHSS sum scores was high with intraclass correlation coefficients of 0.99 (95% CI: 0.987-1.00) for 4G and 0.98 (95% CI: 0.96-0.99) for 3G. None of the remote treatment decisions differed from onsite decisions. CONCLUSIONS: 4G mobile communications provided higher quality of video-examination and allowed reliable remote assessment of stroke symptoms but coverage was still incomplete in both networks.

Kras(G12D) induces EGFR-MYC cross signaling in murine primary pancreatic ductal epithelial cells.

Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas.

Clinical evaluation of a new tracheal impedance cardiography method.

Non-invasive cardiac output measurement by means of impedance cardiography has been evaluated before, and agreement with other methods has been variable. We decided to study a newly developed tracheal impedance device, that is claimed to be more accurate and reliable. This incorporates new software and mathematical formulae, that are designed to reduce signal noise from diathermy, leading to improved accuracy. In 25 cardiothoracic surgery patients, simultaneous measurements were performed using both pulmonary artery thermodilution and the tracheal impedance device, at five peri-operative time points: before skin incision; after weaning from cardiopulmonary bypass; after sternal closure; and 30 min and 2 h after arrival in the intensive care unit. Mean cardiac output, bias and 95% limits of agreement were 5.3, 0.03 and -2.8 to 2.8 l.min(-1) , respectively. Tracheal impedance showed good correlation with measurement trends using thermodilution in 88% of measurements, with a mean (95% limit of agreement) angular bias of -9.0° (-83.3 to 65.3°). However, the wide limits of agreement and high percentage error of 53% that were apparent in this study mean that, in its present guise, tracheal impedance is not an acceptable alternative to thermodilution in cardiac surgical patients.

Characterization of motor and somatosensory function for stroke patients.

In a pilot study, stroke patients with a lesion related to the motor system were studied using magnetoencephalography (MEG) and electromyography (EMG). The patients performed sustained finger movements for 30 s followed by 30 s of rest and 20 repetitions of this sequence in total. Task-related cortical signals derived from MEG were observed here at very different frequency scales. Slow signals below 0.1 Hz were extracted by independent component analysis and are associated with the sustained activation of the motor cortex, the dcMEG motor activation. MEG-EMG coupling phenomena in the 10-30 Hz range were analyzed using the imaginary part of coherency and are attributed to cortico-muscular coupling driving the muscles. Additionally a signal from the somatosensory cortex due to an electrical stimulation at the wrist, the N20m, was recorded as a physiological marker. Field maps and time series associated with the three types of signals are presented for one patient and one control subject as the signal quality of the patient data was not sufficient to achieve a group result. The feasibility of a comprehensive electrophysiological measuring and analysis procedure of the motor function for stroke research is demonstrated by the results.

Extent of spontaneous motor recovery after traumatic cervical sensorimotor complete spinal cord injury.

STUDY DESIGN: Retrospective, longitudinal analysis of motor recovery data from individuals with cervical (C4-C7) sensorimotor complete spinal cord injury (SCI) according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI). OBJECTIVES: To analyze the extent and patterns of spontaneous motor recovery over the first year after traumatic cervical sensorimotor complete SCI. METHODS: Datasets from the European multicenter study about SCI (EMSCI) and the Sygen randomized clinical trial were examined for conversion of American Spinal Injury Association (ASIA) Impairment Scale (AIS) grade, change in upper extremity motor score (UEMS) or motor level, as well as relationships between these measures. RESULTS: There were no overall differences between the EMSCI and Sygen datasets in motor recovery patterns. After 1 year, up to 70% of subjects spontaneously recovered at least one motor level, but only 30% recovered two or more motor levels, with lesser values at intermediate time points. AIS grade conversion did not significantly influence motor level changes. At 1 year, the average spontaneous improvement in bilateral UEMS was 10-11 motor points. There was only moderate relationship between a change in UEMS and a change in cervical motor level (r(2)=0.30, P<0.05). Regardless of initial cervical motor level, most individuals recover a similar number of motor points or motor levels. CONCLUSION: Careful tracking of cervical motor recovery outcomes may provide the necessary sensitivity and accuracy to reliably detect a subtle, but meaningful treatment effect after sensorimotor complete cervical SCI. The distribution of the UEMS change may be more important functionally than the total UEMS recovered.

[Suicide attempt with sotalol: a proarrhythmic intoxication]. / Tentamen suicidii met sotalol: een proaritmische intoxicatie.

A 62-year-old man was brought into the intensive care unit because of a cardiac arrest. After extensive resuscitation, including defibrillation, sinus bradycardia occurred with marked QT prolongation, followed by recurrent episodes of torsade de pointes. Hetero-anamnestic data revealed a suicide attempt with sotalol. Treatment consisted largely of temporary pacing using an external transvenous overdrive pacemaker and administration of glucagon, milrinon and norepinephrine. Eventually, the patient was discharged in good condition. A suicide attempt with sotalol is a rare intoxication with considerable morbidity and mortality. Treatment is primarily based upon counteracting the proarrhythmic effects of sotalol. However, even when therapeutic levels of this drug are used, proarrhythmic effects can occur.

Non-esterified fatty acids impair insulin-mediated glucose uptake and disposition in the liver.

AIMS/HYPOTHESIS: We investigated the effect of elevated circulating NEFA on insulin-mediated hepatic glucose uptake (HGU) and whole-body glucose disposal (M) in eight healthy male subjects. METHODS: Studies were performed using positron emission tomography (PET) and [(18)F]-2-fluoro-2-deoxyglucose ([(18)F]FDG) during euglycaemic hyperinsulinaemia (0-120 min) and an Intralipid/heparin infusion (IL/Hep; -90-120 min). On a different day, similar measurements were taken during euglycaemic hyperinsulinaemia and saline infusion (SAL). Graphical and compartmental analyses were used to model liver data. RESULTS: Circulating NEFA increased approximately three-fold during IL/Hep, and declined by 81+/-7% in the SAL study ( p

Endoscopic treatment of a Zenker's diverticulum using argon plasma coagulation in a patient with massive cachexia and esophageal obstruction: a case report and review of literature.

A case report is presented of an 86-year-old man in a very poor general condition with a 10-year history of a Zenker's diverticulum as a cause of a complete obstruction of the esophagus with subsequent aphagia and massive cachexia. Because of high surgical risk and contraindications to general anesthesia, an approach with the flexible endoscope to perform cricopharyngeal myotomy was undertaken. Several attempts with the flexible endoscope by experienced investigators had been performed until the esophageal inlet was intubated and argon plasma coagulation could be applied in several sessions to divide the tissue bridge between the esophagus and the Zenker diverticulum to successfully restore the pharyngoesophageal passage.

Characterization of vagal input to the rat esophageal muscle.

There is recent morphological evidence for an interaction of autonomic nerve fibers and extrinsic motor nerves of the rat esophagus. The aim of the present study was to investigate a possible functional role of this autonomic innervation of vagal motor fibers on rat esophageal smooth and striated muscle function in vitro. The entire esophagus with both Nn vagi, including the Nn recurrentes, was dissected and placed in an organ bath with oxygenated Krebs-Ringer buffer. Contractile activity was measured in longitudinal direction with a force transducer. Both Nn vagi were placed on a bipolar platinum electrode 2 cm apart from the esophagus. Vagal stimulation, applied for 1 s (40 V, 0.5 ms, 20 Hz) resulted in a biphasic contractile response, which was completely blocked by tetrodotoxin (10(-6) M). The first part consisted of a tetanic striated muscle contraction, which was abolished by tubocurarin (10(-5) M) but unaffected by atropine (10(-6) M) or hexamethonium (10(-4) M). In contrast, the second part was completely abolished by hexamethonium (10(-4) M) and atropine (10(-6) M), whereas tubocurarine (10(-5) M) showed no influence, suggesting a stimulation of preganglionic nerve fibers supplying esophageal smooth muscle (muscularis mucosae). In order to characterize possible autonomic transmitters of the ENS of the esophagus, the following experiments were carried out. The magnitude of the striated muscle response was unaffected by VIP (10(-7) M), 5-HT (10(-6) M) and galanin (10(-8) - 10(-7) M), whereas they caused an inhibition of the smooth muscle response (VIP: -53.8 +/- 4.2%; galanin 10(-8) M: - 18.5 +/- 2.2%; 10(-7) M: -40.4 +/- 2.9%; 5-HT: -78.2 +/- 2.1%). The inhibitory effects of VIP and galanin on smooth muscle were reversible by the antagonists VIP 10-28 and galanin 1-15. In the presence of the nitric oxide synthase (NOS) inhibitor L-NNA (10(-4) M), the smooth and striated muscle contraction were not significantly influenced. Exogenous application of the NO-donor DEA-NO (10(-4) M) reduced the smooth muscle contraction by -81.6 +/- 7.4%, but had no significant effect on the striated muscle contraction. Though immunohistochemical findings are highly suggestive of an nitrergic autonomic modulation of striated muscle contraction by enteric neurons, we could not demonstrate a NO-mediated action on striated muscle activity. Therefore, the physiological relevance of the immunohistochemical findings remain unclear.

The influence of cancellous bone density on load sharing in human lumbar spine: a comparison between an intact and a surgically altered motion segment.

The aim of the current study is twofold: first, to compare load sharing in compression between an intact and a surgically repaired lumbar spine motion segment L3/4 using a biomechanically validated finite element approach; second, to analyse the influence of bone mineral density on load sharing. Six cadaveric human lumbar spine segments (three segments L2/3 and three segments L4/5) were taken from fresh human cadavers. The intact segments were tested under axial compression of 600 N, first without preload and then following instrumented stabilisation. These results were compared to a finite element model simulating the effect of identical force on the intact segments and the segments with constructs. The predictions of both the intact and the surgically altered finite element model were always within one standard deviation of the mean stiffness as analysed by the biomechanical study. Thus, the finite element model was used to analyse load sharing under compression in an intact and a surgically repaired human lumbar spine segment model, using a variety of E moduli for cancellous bone of the vertebral bodies. In both the intact and the surgically altered model, 89% of the applied load passed through the vertebral bodies and the disc if an E modulus of 25 MPa was used for cancellous bone density. Using 10 MPa--representing soft, osteoporotic bone--this percentage decreased, but it increased using 100 MPa in both the intact and the altered segment. Thus, it is concluded that reconstruction of both the disc and the posterior elements with the implants used in the study recreates the ability of the spine to act as a load-sharing construction in compression. The similarity in load sharing between normal and instrumented spines appears to depend on assumed bone density, and it may also depend on applied load and loading history.

Recruitment and early treatment in a multicenter study of acute spinal cord injury.

STUDY DESIGN: Post hoc secondary analysis of data from 1992 to 1998 in the trial of Sygen in Acute Spinal Cord Injury. OBJECTIVES: Quasi-epidemiologic understanding of injury and treatment patterns and of recruitment in an SCI trial. No drug efficacy results. SUMMARY OF BACKGROUND DATA: The most recent large epidemiologic study was the National SCI Database by Stover and colleagues around 1980. METHODS: Emphasis on descriptive, rather than inferential, statistics: consistent with secondary analysis. RESULTS: The study involved 760 patients at 28 centers in North America. Cervical injuries were more common than thoracic, and complete injuries were more common than incomplete injuries. Recruitment in the complete cervical stratum was 332, but the incomplete thoracic strata had only 31 patients combined. Vital signs at arrival and on randomization show fair stability. Clock times show more injuries on weekends and nights but suggest immediate attention was given. Elapsed times to treatment (especially EMT and Medevac arrival) are short. The rate of direct admission to tertiary centers, traction weight, and time to surgery vary among centers. Inpatient rehabilitation appeared driven by insurance in addition to severity. CONCLUSIONS: The imbalances in favor of cervical and of complete injuries would make it hard for studies to attain results for SCI in general. The vital signs and time patterns suggest local protocol-driven stabilization to prevent secondary physiologic injury early after SCI. Some features of care vary among centers, but the sparseness of prospective data in specific injury and treatment categories suggests that treatment guidelines have limited empirical support and should be made cautiously.

Measurements and recovery patterns in a multicenter study of acute spinal cord injury.

STUDY DESIGN: Post hoc, secondary analysis of data from 1992 to 1998 in the trial of Sygen in acute spinal cord injury. OBJECTIVES: Quasi-epidemiologic understanding of measurement tools and of recovery patterns. No drug efficacy results. SUMMARY OF BACKGROUND DATA: Many authors have studied individual scales for measuring the severity of spinal cord injury. METHODS: Emphasis on descriptive, rather than inferential, statistics: consistent with secondary analysis. RESULTS: Of the 760 patients, 43 died within 365 days. The rate was higher for complete injuries (7.1% vs. 3.2%, P = 0.017). Marked recovery at 26 weeks was more frequent in those with better baseline American Spinal Injury Association (ASIA) Impairment Scale (AIS) scores, but was not different for methylprednisolone within versus after 3 hours. Light touch scores improved at each visit, more so in those with higher scores at baseline. Bladder control similarly improved. Motor and sensory scores exhibited departures from assumptions underlying normal-theory statistical techniques: t test and analysis of variance. Furthermore, they were mixtures of differing distributions from different study strata, so that overall conclusions depend on the mixture of patients seen. CONCLUSIONS: The prognosis of these patients with spinal cord injury seen at 28 centers in North America during the mid-1990s appears better than was often assumed earlier. The general patterns are similar across different measurement scales, although there are intriguing differences. The patterns in different strata are different in specifics, and complete injuries do less well. Pooling data from different strata may result in probability distributions that depart from normal-theory assumptions and give misleading results depending on recruitment patterns.